Concerted multi-pronged attack by calpastatin to occlude the catalytic cleft of heterodimeric calpains

Tudor Moldoveanu, Kalle Gehring and Douglas R. Green ()
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Tudor Moldoveanu: St Jude Children’s Research Hospital, 332 N Lauderdale, Memphis, Tennessee 38105, USA
Kalle Gehring: McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada
Douglas R. Green: St Jude Children’s Research Hospital, 332 N Lauderdale, Memphis, Tennessee 38105, USA

Nature, 2008, vol. 456, issue 7220, 404-408

Abstract: Protein digesting enzymes: calpain constrained Calpains are cysteine proteases involved in remodelling protein structures needed for cell movement and division, in response to the release of calcium ions. They regulate cell migration, cell death, insulin secretion, synaptic function and muscle homeostasis. Their endogenous inhibitor, calpastatin, consists of four inhibitory repeats, each of which neutralizes an activated calpain with exquisite specificity and potency. Two papers in this issue present a complete picture of how calpastatin shuts down calpain activity. Moldoveanu et al. determined the crystal structure of calcium-bound m-calpain in complex with the first calpastatin repeat, CID-1. Hanna et al. present the structure of the Ca2+-bound calpain 2 heterodimer bound to one of the other inhibitory domains of calpastatin, CID-IV. This study shows how the inhibitor binds and inhibits calpain only in the presence of calcium. More importantly, since calpastatin is itself a protein, we show the novel way in which calpastatin avoids being cut and destroyed by calpain.

Date: 2008
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DOI: 10.1038/nature07353

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